The present invention relates to a process for the preparation of racemic diphosphines, to a process for the preparation of enantiomerically pure diphosphines, to novel enantiomerically pure diphosphines, to novel intermediates for the preparation of diphosphines, and to catalysts that contain novel diphosphines.
A process that differs greatly from the process according to the invention for the preparation of diphosphines is known from EP-A 749,973. According to this, if the intention is to prepare enantiomerically pure diphosphines, the racemate resolution is carried out at the stage of the phosphine oxides, i.e., for individual diphosphines separate racemate resolutions must be carried out. Compounds different from the compounds according to the invention are described in EP-A 104,375, EP-A 582,692, and EP-A 690,065. Racemate resolutions with N-benzylcinchonidinium chloride have hitherto been described only for dinaphthol compounds (Tetrahedron Lett. 36, 7991 (1995)).
Specifically, the present invention first relates to a process for the preparation of racemic diphosphines of the formula (I) 
in which
R is C6-C14-aryl or C4-C13-heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, wherein the aryl and heteroaryl radicals may optionally be substituted by halogen, C1-C6-alkyl, C1-C6-alkoxy, and/or trimethylsilyl, and
R1 to R4, independently of one another, are each hydrogen, C1-C10-alkyl, C1-C10-alkoxy, F, Cl, or Br, comprising
(a) converting a phenol of the formula (II) 
in which R1 to R4 have the meanings given for formula (I), into the corresponding phenoxide using a base,
(b) reacting the phenoxide with dihalogenomethane to give a formaldehyde acetal of the formula (III) 
in which R1 to R4 have the meanings given for formula (I),
(c) intramolecularly oxidatively coupling the formaldehyde acetal of the formula (III) to give a cycloheptadiene of the formula (IV), 
in which R1 to R4 have the meanings given for formula (I),
(d) converting the cycloheptadiene of the formula (IV) by treatment with an acid into a biphenyldiol of the formula (V) 
in which R1 to R4 have the meanings given for formula (I),
(e) preparing the corresponding triflate from the biphenyldiol of the formula (V), and
(f) coupling the triflate with a secondary phosphine of the formula (VI)
HPR2xe2x80x83xe2x80x83(VI), 
in which R has the meaning given for formula (I),
with the addition of a base and in the presence of a palladium(0), palladium(II), nickel(0), and/or Ni(II) compound, thereby giving a compound of the formula (I).
In the formulas (I) to (V), R1 and R2 are preferably hydrogen and R3 and R4 are preferably C1-C5-alkoxy, fluorine, or chlorine. In the formulas (I) and (VI), R is preferably phenyl, furyl, or 2-N-C1-C6-alkylpyrrolyl that may optionally be substituted by 1 to 3 substituents from the group consisting of fluorine, chlorine, C1-C5-alkyl, C1-C6-alkoxy, and trimethylsilyl. In the formulas (I) to (V), R1 and R2 are particularly preferably hydrogen, R3 is particularly preferably chlorine, and R4 is particularly preferably methoxy or ethoxy. In the formulas (I) and (VI), R is particularly preferably phenyl, 2-furyl, 2-N-methylpyrrolyl, 3,5-dimethylphenyl, 4-fluorophenyl, 4-tolyl, or 3,5-dimethoxyphenyl.
In the conversion of the phenol of the formula (II) into the corresponding phenoxide, the base that can be used is, for example, an alkali metal hydride, hydroxide, or carbonate. Preference is given to sodium hydride and potassium hydride. The base is preferably used in an amount of from 0.9 to 1.5 equivalents per mole of phenol of the formula (II). Here, it is possible to work in the presence of a solvent, e.g., in the presence of a dipolar-aprotic solvent, such as dimethylformamide, or an ether, such as diethyl ether, tetrahydrofuran, dioxane, or methyl tert-butyl ether.
Suitable reaction temperatures, particularly when alkali metal hydrides are used as base, are, for example, those in the range from xe2x88x9220 to +60xc2x0 C. It is advantageous to carry out this stage under a protective gas atmosphere. The procedure may involve, for example, initially introducing the base together with the solvent and metering in the phenol of the formula (II) dissolved in the same solvent.
The phenoxide obtained does not need to be isolated. Particularly if the process has been carried out with stoichiometric amounts of alkali metal hydride as base, the reaction mixture that is present following reaction with the base can be further used directly.
In the reaction with the phenoxide it is possible to use, based on one mole of phenol of the formula (II) originally used, e.g., 0.4 to 0.7 mol of dihalogenomethane. Suitable reaction temperatures are, for example, those from 0 to 80xc2x0 C., particularly those from 10 to 60xc2x0 C. The reaction time for the reaction with the dihalogenomethane can be, for example, 8 to 40 hours. Suitable as dihalogenomethane is, for example, dichloromethane, dibromomethane, and diiodomethane. Diiodomethane is preferred.
The reaction mixture that is then present can be worked up, for example, by extracting it after addition of water with a virtually nonpolar or nonpolar organic solvent and removing the solvent from the extract. The residue that remains can, if desired, be further purified, for example, by dissolving it in an ether, in methanol, or in acetonitrile at elevated temperature, discarding the insoluble components, and obtaining the prepared formaldehyde acetal of the formula (III) in purified form by crystallization.
The intramolecular oxidative coupling for the preparation of a cycloheptadiene of the formula (IV) can be carried out, for example, by first adding an organolithium compound to the formaldehyde acetal of the formula (III) and, when they have finished reacting, adding an oxidizing agent. For example, it is possible to add butyllithium dissolved in, for example, a hydrocarbon to a solution of the formaldehyde acetal, for example in ether, at xe2x88x9230 to +40xc2x0 C. and leave the mixture to fully react by after-stirring at a temperature in this range. Per mole of formaldehyde acetal, it is possible to use, for example, 2.0 to 2.2 mol of organolithium compound. In general, the reaction is complete after 5 to 30 hours. The oxidizing agent can then be added, for example a Cu(II), Fe(III), Mn(III), or Ce(IV) compound. The oxidative coupling can also be carried out enzymatically, e.g., with a peroxidase. The oxidizing agent is added at, for example, xe2x88x9270 to xe2x88x9230xc2x0 C., and the mixture is subsequently warmed to a temperature of, for example, below 50xc2x0 C. Based on 1 mol of formaldehyde acetal of the formula (III) used, it is possible to use, for example, 2.0 to 2.5 equivalents of an oxidizing agent. It is advantageous to continue to after-stir the reaction mixture in conclusion, e.g., for 1 to 5 hours.
It is also possible to carry out the oxidative coupling directly from the formaldehyde acetal of the formula (III) in accordance with the methods described here without converting said formaldehyde acetal into the Li salt beforehand.
It is advantageous at least to carry out the reaction with the organolithium compound under a protective gas atmosphere.
The treatment with an acid to convert a cycloheptadiene of the formula (IV) into a biphenyldiol of the formula (V) can be carried out, for example, with a strong mineral acid such as hydrochloric acid or sulfuric acid. For example, 5 to 15 equivalents of acid can be used per mole of cycloheptadiene of the formula (IV). The procedure is expediently carried out in the presence of a solvent, for example in the presence of an alcohol. The treatment with the acid can be carried out, for example, in a period of from 5 to 50 hours at temperatures of from 50 to 100xc2x0 C. The reaction mixture can be worked up, for example, analogously to the procedure described above for the preparation of formaldehyde acetals of the formula (III).
The preparation of the triflate compound (i.e., a trifluoromethanesulfonic ester) from the biphenyldiol of the formula (V) can be carried out, for example, by suspending the biphenyldiol of the formula (V) in a solvent (e.g., an aromatic hydrocarbon), adding a tertiary amine (e.g. pyridine), and then metering in, for example, trifluoromethanesulfonic anhydride or trifluoromethanesulfonyl chloride, optionally dissolved in a solvent (e.g., in an aromatic hydrocarbon), and after-stirring. The metered addition and after-stirring can be carried out, for example, at 0 to 60xc2x0 C. A suspension forms during this operation. Per mole of biphenyldiol of the formula (V), it is possible to use, for example, 2 to 3 mol of a tertiary amine and 2 to 2.2 mol of trifluoromethanesulfonic anhydride or trifluoromethanesulfonyl chloride.
For work-up, the reaction mixture can, for example, be washed with water and aqueous sodium chloride solution, the organic phase that is left behind can be dried, and the solvent can be removed, where necessary by stripping it off under reduced pressure. The product obtainable in this way is pure enough for the reaction with secondary phosphines. If desired, it can be further purified, e.g., by (flash) column chromatography.
For the reaction of the triflate compound with a secondary phosphine of the formula (VI), the base that may be used is, for example, a tertiary amine (for example, a trialkylamine), that contains three identical or different C1-C6-alkyl groups. Arylalkylamines, DABCO, xe2x80x9cproton spongesxe2x80x9d (e.g. 1,8-bis(dimethylamino)naphthalene) and hydrogen carbonates, such as sodium hydrogen carbonate, are also possible. Preference is given to using triethylamine or ethyl-diisopropyl-amine. The amount of base used, based on one mole of the triflate compound, can, for example, be 2 to 3 mol.
Suitable palladium(0) or nickel(0) compounds are, for example complexes of the formulas (VIIa) and (VIIb),
Pd(PRxe2x80x23)4xe2x80x83xe2x80x83(VIIa) 
Ni(PRxe2x80x23)4xe2x80x83xe2x80x83(VIIb) 
in which
Rxe2x80x2 is in each case C1-C10-alkyl or C6-C14-aryl, where aryl may optionally be substituted by halogen and/or C1-C6-alkyl, and where Rxe2x80x2 is preferably phenyl.
Also suitable as palladium(0) compound is Pd2(dba)3, where dba is dibenzylideneacetone. The Pd2(dba)3 can optionally also contain a coordinated solvent molecule, e.g., CHCl3.
It is also possible to use a palladium(0) compound of the formula (VIIc)
Pd(L2)xe2x80x83xe2x80x83(VIIc), 
in which
L is Rxe2x80x22Pxe2x80x94(CH2)nxe2x80x94PRxe2x80x22, diphenylphosphinoferrocenyl, or 2,2xe2x80x2-bis(diphenylphosphinomethyl)-1,1xe2x80x2-binaphthyl, where Rxe2x80x2 has the meaning given above and n is 1, 2, 3, or 4.
Preferred compounds of the formula (VIIc) are those in which L is Rxe2x80x22Pxe2x80x94(CH2)nxe2x80x94PRxe2x80x22, where Rxe2x80x2 is phenyl and n is 2, 3, or 4.
Suitable as palladium(II) compound is, for example, Pd(CH3COO)2, and suitable as nickel(II) compound, for example, NiCl2 that optionally also contains 1 to 2 coordinated PRxe2x80x23-molecules (where Rxe2x80x2 has the same meaning as in the formulas (VIIa) and (VIIb)).
Preference is given to using palladium(0) compounds of the formulas (VIIa) and (VIIc) and Pd2(dba)3. These compounds can, if desired, also be prepared in situ, for example, by initially introducing palladium diacetate into a solvent and adding the ligands in the stoichiometrically required amount or in an excess of up to, for example, 150% of the stoichiometrically required amount.
The amount of palladium and/or nickel compounds used, based on 1 mol of triflate compound, can be, for example, 0.001 to 0.1 mol.
The reaction of the triflate compound with a secondary phosphine of the formula (VI) can be carried out, for example, by initially producing the palladium(0), palladium(II), nickel(0), and/or nickel(II) compound in a dipolar-aprotic solvent or preparing said compound in situ in a dipolar-aprotic solvent, and then bringing it together with the secondary phosphine of the formula (VI), the base, the triflate compound, and optionally further solvent. It is also possible to prepare a mixture as described above that contains the palladium and/or nickel compound, to add this mixture to an initial charge of triflate compound, and then to add base, secondary phosphine of the formula (VI), and optionally further solvent. The preparation of the mixture containing palladium and/or nickel compounds can be carried out, for example, at xe2x88x9210 to +40xc2x0 C., and the reaction with the triflate compound can be carried out at, for example, 20 to 160xc2x0 C. The reaction of the triflate compound can require, for example, reaction times in the range from 5 to 200 hours.
Isolation and purification of the diphosphine compound of the formula (I) prepared in this way can be carried out, for example, by first stripping off the solvent at elevated temperature under reduced pressure, taking up the residue with toluene, passing this mixture over a silica column, taking the fraction containing the prepared diphosphine, stripping off the toluene therefrom, dissolving the residue in dimethylformamide, and crystallizing the prepared diphosphine by layering with methanol or dialkyl ether.
The present invention further relates to a process for the preparation of enantiomerically pure diphosphines of the formula (VIII) 
in which the symbols used have the meanings given for formula (I), and of a formula that is analogous to formula (VIII) but represents the other enantiomer.
This preparation is carried out according to the invention like the above-described preparation of the racemic diphosphines of the formula (I) and is additionally characterized in that the biphenyldiol of the formula (V) is subjected to racemate resolution. The racemate resolution can be carried out, for example, by crystallization using an auxiliary reagent or by chiral chromatography, e.g., according to the SMB method. Suitable auxiliary reagents for the racemate resolution by crystallization are, for example, tartaric acid derivatives and cinchonine derivatives.
For this purpose, preference is given to using (xe2x88x92)-O,Oxe2x80x2-dibenzoyl-L-tartaric acid or enantiomerically pure N-benzylcinchonidinium chloride. Per mole of biphenyldiol, it is possible to use, for example, 0.5 to 1 mol of auxiliary reagent.
The racemate resolution can, for example be carried out by refluxing the racemic biphenyldiol of the formula (V) together with the auxiliary reagent in a suitable solvent, e.g., a C1-C4-alkyl alcohol or acetonitrile for a few hours, after-stirring, filtering off the precipitate that is present, and taking it up in a water-immiscible solvent (e.g., a chloro-alkane, an aromatic hydrocarbon, or ethyl acetate), washing with an acid, e.g., a dilute mineral acid, separating off the organic phase, extracting the aqueous phase with a water-immiscible solvent, and stripping off the solvent from the combined organic phases.
The remaining preparation of enantiomerically pure diphosphines of the formula (VIII) is then carried out as described above for the preparation of racemic diphosphines.
The present invention further relates to enantiomerically pure diphosphines of the formula (IX) 
in which the radicals Rxe2x80x3 are in each case identical and are 2-furyl, 2-N-methylpyrrolyl, 4-fluorophenyl, 3,5-dimethoxyphenyl, or 3,5-dimethylphenyl, and of a formula that is analogous to formula (IX) but represents the other enantiomer.
The present invention further relates to cycloheptadiene compounds of the formula (IV), to racemic and enantiomerically pure biphenyldiols of the formula (V), and to the corresponding racemic and enantiomerically pure triflate compounds accessible from the biphenyldiols of the formula (V), wherein in the triflate compounds in each case R1 and R2 are H, R3 is chlorine, and R4 is methoxy.
The racemic diphosphines of the formula (I) prepared according to the invention and the novel enantiomerically pure (+)- and (xe2x88x92)-diphosphines of the formula (VIII) are suitable as ligands for the preparation of catalysts, preferably of catalysts for hydrogenation. The enantiomerically pure (+)- and (xe2x88x92)-diphosphines of the formula (VIII) are particularly suitable as ligands for the preparation of hydrogenation catalysts for enantioselective hydrogenations.
Said ligands may, in order to be successful as hydrogenation catalysts, be combined with metals, including in the form of metal ions or metal complexes of elements of subgroup VIII of the Periodic Table of the Elements. In this connection, ruthenium, iridium, and rhodium are preferred. Here, the ligand-metal combination may be undertaken separately or in situ within the reaction mixture for the hydrogenation. In this connection, 0.5 to 10 mol (preferably 1 to 5 mol) of said ligands, for example, may be used per mole of metal.
The racemic diphosphines of the formula (I) can, for example, be used advantageously as ligands for palladium catalysts used in amination reactions. Numerous intermediates for pharmaceutical and crop protection active ingredients are accessible by palladium-complex-catalyzed aminations. It has hitherto been known to use binaphthylphosphorus compounds as ligands for such aminations.
Finally, the present invention also relates to catalysts that contain a metal, a metal ion or a metal complex of an element of subgroup VIII of the Periodic Table of the Elements and at least one diphosphine of the formula (IX). These catalysts preferably contain, independently of one another, ruthenium, iridium, or rhodium and 0.5 to 10 mol of a diphosphine of the formula (IX) per mole of metal, metal ion, or metal complex.
In the process according to the invention for the preparation of racemic diphosphines of the formula (I), it is advantageous that a broad palette of different ligands is accessible directly from one precursor (i.e., a compound of the formula (VI)). For example, it is readily possible to prepare different ligands, tailored to a specific catalyst problem, that have different electronic and steric ratios.
In the process according to the invention for the preparation of enantiomerically pure diphosphines of the formula (VIII), it is advantageous that the phosphine radicals are introduced only after the racemate resolution. As a result, it is possible to carry out the complex racemate resolution for diverse diphosphines in a common initial stage and only then prepare a broad spectrum of individual diphosphines. Separate racemate resolutions for individual diphosphines can thus be avoided.
The enantiomerically pure diphosphines of the formula (IX) according to the invention have the advantage that catalysts that can be prepared therefrom are superior to other catalysts in different reactions with regard to the enantiomer excess that is achievable following their use. Ruthenium catalysts with enantiomerically pure ligands according to the invention are, for example, advantageous for the enantioselective hydrogenation of heteroaromatic ketones and itaconic acid derivatives.
The cycloheptadiene compounds, biphenyldiols, and triflate compounds according to the invention are novel intermediates for the preparation of novel diphosphines, from which catalysts with superior properties can be prepared.
The following examples further illustrate details for the process of this invention. The invention, which is set forth in the foregoing disclosure, is not to be limited either in spirit or scope by these examples. Those skilled in the art will readily understand that known variations of the conditions of the following procedures can be used. Unless otherwise noted, all temperatures are degrees Celsius and all percentages are percentages by weight.